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Purpose: Uterine sarcomas are a rare group of uterine malignancies. Due to the low incidence and changes in uterine sarcoma classification, risk factors are not well characterized. Our objective was to evaluate risk factors for uterine sarcoma and compare risk factors between uterine sarcoma, malignant mixed Mullerian tumors (MMMTs), and type I endometrial carcinomas., Methods: This nested case-control study utilized linked data from population-based medical birth and cancer registries in Denmark, Finland, Norway, and Sweden. Up to 10 controls were matched on country and birth year for each uterine cancer case. Using multivariable adjusted multinomial logistic regression, estimates of the associations between pregnancy-related factors and risk of uterine sarcoma, MMMTs, and type I endometrial carcinomas were determined., Results: Having a very-low-birth-weight infant (< 1500 vs. 2500-3999 g: OR [95% CI] 2.83 [1.61-4.96]) was associated with an increased risk of uterine sarcoma. Whereas, having a more recent pregnancy was associated with reduced risks of MMMT (< 10 vs. ≥ 30 years: 0.66 [0.20-2.23]) and type 1 endometrial carcinomas (0.35 [0.30-0.41]) but not uterine sarcomas (1.33 [0.90-1.98], p-heterogeneity < 0.01)., Conclusion: Our study provides evidence that risk factors for uterine sarcoma and MMMT, previously grouped with uterine sarcomas, vary substantially. Additionally, MMMT and type I endometrial carcinomas are more similar than uterine sarcoma in that pregnancy complications like gestational hypertension and preeclampsia were associated with reduced risks of both but not uterine sarcoma, suggesting different etiologies., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Ovarian cancer is associated with high serum calcium and low serum albumin in clinical and epidemiologic studies. Whether high calcium and low albumin predispose to ovarian cancer or reflect existing cancer is unclear., Objective: Test the hypothesis that serum calcium increases and serum albumin decreases in women who develop ovarian cancer., Methods: Two hundred and four women donated sera to the Janus Serum Bank in Norway pre- and post-diagnosis of ovarian cancer, donations separated by approximately 14 years. We measured calcium and albumin in these sera and calculated the albumin-corrected calcium. Sera were adjusted for patient age and storage time., Results: Post-diagnosis, mean age- and storage-adjusted calcium increased, from 2.53 to 2.68 mmol/L (p < .001). Mean age- and storage-adjusted, albumin-corrected calcium increased from 2.3 to 2.7 mmol/L (p < .001). Conversely, mean age- and storage-adjusted albumin decreased, from a mean of 51.3 to 40.9 g/L (p < .001). Significant changes were observed in women with early stage and metastatic cancer., Conclusions: These data support the hypothesis that calcium and albumin are serum biomarkers of extant ovarian cancer. Longitudinal changes in calcium and albumin may be useful in ovarian cancer early detection., Competing Interests: Declaration of Competing Interest GGS is an inventor on a US patent on the detection of ovarian cancer that involves calcium and albumin. No potential conflicts were disclosed by the other authors., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: High birthweight may predispose children to acute lymphoid leukemia, whereas low birthweight is associated with childhood morbidity and mortality. Low and high birthweight have been inconsistently associated with mortality in children with leukemia. Material and methods: In a cohort of childhood and adolescent leukemia (0-19 years) patients from registries in Denmark, Norway, Sweden, and Washington State in the United States (1967-2015), five-year all-cause mortality was assessed by birthweight and other measures of fetal growth using the cumulative incidence function and Cox regression with adjustment for sex, diagnosis year, country, the presence of Down's syndrome or other malformations, and type of leukemia. Results: Among 7148 children and adolescents with leukemia (55% male), 4.6% were low (<2500 g) and 19% were high (≥4000 g) birthweight. Compared with average weight, hazard ratios (HRs) of death associated with low birthweight varied by age at leukemia diagnosis: 1.5 (95% confidence interval (CI): 0.7, 3.2) for patients 0-1 year old, 1.6 (95% CI: 1.0, 2.6) for >1-2 years old; 1.0 (95% CI: 0.6, 1.5) for 3-8 years old; 1.0 (95% CI: 0.6, 1.8) for 9-13 years old; and 1.2 (95% CI: 0.7, 2.1) for 14-19 years old, and were similar for size for gestational age and Ponderal index. In analyses restricted to children born full term (37-41 weeks of gestation), results were only slightly attenuated but risk was markedly increased for infants aged ≤1 year (HR for low birthweight = 3.2, 95% CI: 1.2, 8.8). Conclusion: This cohort study does not suggest that low birthweight or SGA is associated with increased five-year all-cause mortality risk among children with any type of childhood leukemia or acute lymphoblastic leukemia, specifically, beyond infancy.

Cancer prevention efforts include modification of unhealthy lifestyle, such as smoking cessation and resisting gain in body weight. Although physical activity is inversely related to risk of several cancers, it is poorly studied whether changes in physical activity or fitness influence future cancer risk. Thus, we aimed to investigate whether changes in midlife cardiorespiratory fitness (CRF), body mass index (BMI), and smoking habits influence cancer incidence and mortality. The study cohort includes 1689 initially healthy men, aged 40-59 years. Measurements of CRF, BMI and information on smoking habits were collected in two repeated waves, 7 years apart. Cox regression models estimated associations as hazard rates (HR) with 95% confidence intervals (CI), between midlife changes in the modifiable lifestyle factors and cancer incidence and mortality. The men were followed prospectively for more than 30 years. Compared to CRF loss (>5%), improved CRF (>5%) was associated with lower cancer incidence (HR 0.81, 95% CI 0.67-0.98) and mortality (HR 0.70, 95% CI 0.54-0.92), and maintaining the CRF stable yielded lower cancer incidence (HR 0.76, 95% CI 0.61-0.95). No association was seen for BMI gain, but maintaining the BMI stable was related to lower cancer incidence (HR 0.77, 95% CI 0.60-0.98), compared to BMI loss. Continue smoking was associated with higher cancer incidence and mortality, compared to men who stopped smoking. In particular, this study adds new knowledge about the potential preventive role of CRF in cancer development and emphasizes lifestyle modification as a highly important effort in cancer prevention., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aims: United States' (US) colorectal cancer (CRC) screening and treatment practices seek to reduce mortality. We examined the survival of US patients compared with patients in the virtually unscreened Norwegian population. Methods: We compared short-term survival after CRC between the US and Norway using relative survival (RS) and excess mortality (EMR) analyses. The CRC patients were aged 50 and older diagnosed in the US (Surveillance, Epidemiology and End Results registry, 2004, N=9511) and in Norway (Cancer Registry of Norway, 2003-2005, N=8256). Results: Death occurred within three years for 39% of the CRC patients. Stage distributions were more favorable for US patients. Stage-specific survival was similar for localized and regional cancers, but more favorable for US distant cancers. In multivariate models of patient, tumor and treatment characteristics, patients (especially below age 80) in the US experienced longer survival (EMR 0.9, CI 0.8-0.9). Stage-specific analyses showed, however, that survival for localized cancers was relatively shorter in the US than in Norway (EMR 1.4, CI 1.1-1.8), but longer for distant cancers (EMR 0.8, CI 0.7-0.8). The enhanced survival for US CRC patients likely reflects a screening-related earlier diagnostic stage distribution, as well as prioritized life extension for patients with metastatic cancers, reflecting vastly different health care systems in the two countries. CRC screening is currently under consideration in Norway. For survival outcomes, the current findings do not discourage such an implementation. Other screening-related aspects such as feasibility and cost-benefit are, however, also relevant and warrant further research within a socialized health system.Conclusions: The enhanced survival for US CRC patients likely reflects a screening-related earlier diagnostic stage distribution, as well as prioritized life extension for patients with metastatic cancers, reflecting vastly different health care systems in the two countries. CRC screening is currently under consideration in Norway. For survival outcomes, the current findings do not discourage such an implementation. Other screening-related aspects such as feasibility and cost-benefit are, however, also relevant and warrant further research within a socialized health system.

Purpose: Breast cancer risk associated with pregnancy characteristics may be mediated by maternal hormones or angiogenic factors., Methods: We conducted a prospective breast cancer case-control study among women in the Avon Longitudinal Study of Parents and Children (ALSPAC) and Norwegian Mother and Child Cohort Study (MoBa) related to maternal pregnancy prolactin (n = 254 cases and 374 controls), placental growth factor (PlGF, n = 252 and 371), soluble fms-like tyrosine kinase-1 (sFlt-1, n = 118 and 240) and steroid hormone concentrations (ALSPAC only, n = 173 and 171). Odds ratios (OR) and 95% confidence intervals (CI) for a 1 SD change in analytes were estimated using unconditional logistic regression with matching factors (cohort, mother's birth year, serum/plasma, blood collection timing) and gestational age., Results: Breast cancer ORs (95% CI) were 0.85 (0.51-1.43) for estradiol, 0.86 (0.67-1.09) for testosterone, 0.89 (0.71-1.13) for androstenedione, 0.97 (0.71-1.34) for hCG, 0.93 (0.75, 1.15) for prolactin, 1.00 (0.78-1.27) for PlGF and 1.91 (1.00-3.65 ALSPAC) and 0.94 (0.73-1.21 MoBa) for sFlt-1, and were similar adjusting for potential confounders. Results were similar by blood collection timing, parity, age at first birth or diagnosis, and time between pregnancy and diagnosis., Conclusion: These data do not provide strong evidence of associations between maternal hormones or angiogenic factors with subsequent maternal breast cancer risk.

Previous studies on metabolic factors and bladder cancer (BC) risk have shown inconsistent results and have commonly not investigated associations separately by sex, smoking, and tumor invasiveness. Among 811,633 participants in six European cohorts, we investigated sex-specific associations between body mass index (BMI), mid-blood pressure (BP, [systolic + diastolic]/2), plasma glucose, triglycerides, total cholesterol and risk of BC overall, non-muscle invasive BC (NMIBC) and muscle invasive BC (MIBC). Among men, we additionally assessed additive interactions between metabolic factors and smoking on BC risk. During follow-up, 2,983 men and 754 women were diagnosed with BC. Among men, triglycerides and BP were positively associated with BC risk overall (hazard ratio [HR] per standard deviation [SD]: 1.17 [95% confidence interval (CI) 1.06-1.27] and 1.09 [1.02-1.17], respectively), and among women, BMI was inversely associated with risk (HR: 0.90 [0.82-0.99]). The associations for BMI and BP differed between men and women (p interaction ≤ 0.005). Among men, BMI, cholesterol and triglycerides were positively associated with risk for NMIBC (HRs: 1.09 [95% CI 1.01-1.18], 1.14 [1.02-1.25], and 1.30 [1.12-1.48] respectively), and BP was positively associated with MIBC (HR: 1.23 [1.02-1.49]). Among women, glucose was positively associated with MIBC (HR: 1.99 [1.04-3.81]). Apart from cholesterol, HRs for metabolic factors did not significantly differ between MIBC and NMIBC, and there were no interactions between smoking and metabolic factors on BC. Our study supports an involvement of metabolic aberrations in BC risk. Whilst some associations were significant only in certain sub-groups, there were generally no significant differences in associations by smoking or tumor invasiveness., (© 2018 UICC.)

Epithelial ovarian cancer is a fatal disease of largely unknown etiology. Higher parity is associated with reduced risk of ovarian cancer. However, among parous women, the impact of pregnancy-related factors on risk is not well understood. This population-based case-control study included all parous women with epithelial ovarian cancer in Denmark, Finland, Norway and Sweden during 1967-2013 (n = 10,957) and up to 10 matched controls (n = 107,864). We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for pregnancy-related factors and ovarian cancer risk by histological subtype. Preterm delivery was associated with an increased risk [pregnancy length (last pregnancy) ≤30 vs. 39-41 weeks, OR 1.33 (95% CI 1.06-1.67), adjusted for number of births]; the OR increased as pregnancy length decreased (p for trend < 0.001). Older age at first and last birth was associated with a decreased risk [first birth: 30-39 vs. <25 years: adjusted OR 0.76 (95% CI 0.70-0.83); last birth 30-39 vs. <25 years: adjusted OR 0.76 (95% CI 0.71-0.82)]. Increasing number of births was protective [≥4 births vs. 1; OR 0.63 (95% CI 0.59-0.68)] for all subtypes, most pronounced for clear-cell tumors [OR 0.30, (95% CI 0.21-0.44), p heterogeneity  < 0.001]. No associations were observed for multiple pregnancies, preeclampsia or offspring size. In conclusion, in addition to high parity, full-term pregnancies and pregnancies at older ages were associated with decreased risk of ovarian cancer. Our findings favor the cell clearance hypothesis, i.e. a recent pregnancy provides protection by clearing of precancerous cells from the epithelium of the ovary/fallopian tubes, mediated by placental or ovarian hormones., (© 2018 UICC.)

Certain features of pregnancy are important risk factors for breast cancer, such as protection afforded by young age at first birth. Preeclampsia, a pregnancy complication, is associated with reduced maternal breast cancer risk. However, questions remain regarding causality, biological mechanisms and the relation of other hypertensive conditions to risk. We conducted a population-based case-control study of breast cancer cases (n = 116,196) in parous women identified through linkage of birth and cancer registries in Denmark, Finland, Norway and Sweden (1967-2013), including up to 10 matched controls per case (n = 1,147,192) sampled from the birth registries (complete data were not available on all variables). Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models including matching factors (country, maternal birth year) and parity. Hypertension diagnosed before pregnancy (OR 0.87; 95% CI 0.78-0.97), gestational hypertension (OR 0.90; 95% CI 0.86-0.93) and preeclampsia (OR 0.91; 95% CI 0.88-0.95) were associated with reduced breast cancer risk. Results remained similar after adjustment for smoking and maternal body mass index before first pregnancy, and were generally similar stratified by parity, age at breast cancer diagnosis, time since first and last birth, sex of the offspring and calendar time. Except for retained placenta (OR 1.14; 95% CI 0.98-1.32), no other pregnancy complication appeared associated with breast cancer risk. The mechanisms mediating the modest risk reductions for history of preeclampsia or hypertension preceding or arising during pregnancy, and possible increased risk with history of retained placenta are unknown and warrant further laboratory, clinical and epidemiological investigation., (© 2018 UICC.)

Background: Maternal predictors of folic acid (FA) supplementation use to reduce offspring risk of neural tube defects are well known, while paternal determinants for maternal FA use are less known. Such knowledge is important to increase women's compliance to recommended periconceptional FA use., Methods: In a nation-wide study of 683,785 births registered in the Medical Birth Registry of Norway during 1999-2010, the associations between paternal characteristics (age, education, occupation, country of origin) and maternal FA use were estimated by relative risks (RR) with 95% confidence intervals (CI), using log-binomial regression., Results: Maternal FA use before and during pregnancy (adequate FA use) was found in 16% of the births. The association between paternal age and adequate FA use was inversely U-shaped; adjusted RRs for adequate FA use were 0.35 (95% CI 0.28-0.43) and 0.72 (95% CI 0.71-0.74) for paternal age < 20 and ≥ 40 years, respectively, comparing age 30-34 years. Compulsory education (1-9 years) among fathers was compared to tertiary education; the RR was 0.69 (95% CI 0.68-0.71) for adequate FA use. The lower risk of adequate FA use for paternal compulsory education was present in all categories of maternal education. Occupation classes other than "Higher professionals" were associated with decreased risk of adequate FA use, compared with the reference "Lower professionals". RR for adequate FA use was 0.58 (95% CI 0.56-0.60) comparing fathers from "Low/middle-income countries" with fathers born in Norway., Conclusion: Adequate FA use in the periconceptional period was lower when fathers were younger or older than 30-34 years, had shorter education, had manual or self-employed occupations, or originated from low/middle-income countries. Partners may contribute to increase women's use of periconceptional FA supplementation.

Background: Breast cancer comprises several molecular subtypes with different prognoses and possibly different etiology. Reproductive and hormonal factors are associated with breast cancer overall, and with luminal subtypes, but the associations with other subtypes are unclear. We used data from a national screening program to conduct a large nested case-control study., Methods: We conducted a nested case-control study on participants in the Norwegian Breast Cancer Screening Program in 2006 - 2014. There was information on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) for 4748 cases of breast cancer. Breast cancer subtypes were defined as luminal A-like (ER+ PR+ HER2-), luminal B-like (ER+ PR- HER2- or ER+ PR+/PR-HER2+), HER2-positive (ER- PR- HER2+) and triple-negative (ER- PR- HER2-). Conditional logistic regression was used to estimate odds ratios (ORs) of breast cancer associated with age at first birth, number of pregnancies, oral contraceptive use, intrauterine devices and menopausal hormone therapy. Analyses were adjusted for age, body mass index, education, age at menarche, number of pregnancies and menopausal status., Results: Number of pregnancies was inversely associated with relative risk of luminal-like breast cancers (p-trend ≤0.02), and although not statistically significant, with HER2-positive (OR = 0.60, 95% CI 0.31-1.19) and triple-negative cancer (OR = 0.70, 95% CI 0.41-1.21). Women who had ≥4 pregnancies were at >40% lower risk of luminal-like and HER2-positive cancers than women who had never been pregnant. However, there was a larger discrepancy between tumor subtypes with menopausal hormone use. Women who used estrogen and progesterone therapy (EPT) had almost threefold increased risk of luminal A-like cancer (OR = 2.92, 95% CI 2.36-3.62) compared to never-users, but were not at elevated risk of HER2-positive (OR = 0.88, 95% CI 0.33-2.30) or triple-negative (OR = 0.92, 95% CI 0.43 - 1.98) subtypes., Conclusions: Reproductive factors were to some extent associated with all subtypes; the strongest trends were with luminal-like subtypes. Hormone therapy use was strongly associated with risk of luminal-like breast cancer, and less so with risk of HER2-positive or triple-negative cancer. There are clearly some, but possibly limited, etiologic differences between subtypes, with the greatest contrast between luminal A-like and triple-negative subtypes., Trial Registration: Not applicable.

Purpose: The association between vegetable and fruit consumption and risk of cancer and cardiovascular disease (CVD) has been investigated by several studies, whereas fewer studies have examined consumption of vegetables and fruits in relation to all-cause mortality. Studies on berries, a rich source of antioxidants, are rare. The purpose of the current study was to examine the association between intake of vegetables, fruits and berries (together and separately) and the risk of all-cause mortality and cause-specific mortality due to cancer and CVD and subtypes of these, in a cohort with very long follow-up., Methods: We used data from a population-based prospective Norwegian cohort study of 10,000 men followed from 1968 through 2008. Information on vegetable, fruit and berry consumption was available from a food frequency questionnaire. Association between these and all-cause mortality, cause-specific mortality due to cancers and CVDs were investigated using Cox proportional hazard regression models., Results: Men who in total consumed vegetables, fruit and berries more than 27 times per month had an 8-10% reduced risk of all-cause mortality compared with men with a lower consumption. They also had a 20% reduced risk of stroke mortality. Consumption of fruit was inversely related to overall cancer mortality, with hazard rate ratios of 0.94, 0.84 and 0.79 in the second, third and firth quartile, respectively, compared with the first quartile., Conclusion: Increased consumption of vegetables, fruits and berries was associated with a delayed risk of all-cause mortality and of mortality due to cancer and stroke.

Adult height and body weight are positively associated with breast cancer risk after menopause, but few studies have investigated these factors according to molecular breast cancer subtype. A total of 18,562 postmenopausal Norwegian women who were born between 1886 and 1928 were followed up for breast cancer incidence from the time (between 1963 and 1975) height and weight were measured until 2008. Immunohistochemical and in situ hybridization techniques were used to subtype 734 incident breast cancer cases into Luminal A, Luminal B [human epidermal growth factor receptor 2 (HER2-)], Luminal B (HER2+), HER2 subtype, basal-like phenotype (BP) and five-negative phenotype (5NP). We used Cox regression analysis to assess adult height and body mass index (BMI) in relation to risk of these subtypes. We found a positive association of height with risk of Luminal A breast cancer (ptrend , 0.004), but there was no clear association of height with any other subtype. BMI was positively associated with risk of all luminal breast cancer subtypes, including Luminal A (ptrend , 0.002), Luminal B (HER2-) (ptrend , 0.02), Luminal B (HER2+) (ptrend , 0.06), and also for the HER2 subtype (ptrend , 0.04), but BMI was not associated with risk of the BP or 5NP subtypes. Nonetheless, statistical tests for heterogeneity did not provide evidence that associations of height and BMI differed across breast cancer subtypes. This study of breast cancer risk among postmenopausal women suggests that height is positively associated with risk of Luminal A breast cancer. BMI is positively associated with risk of all luminal subtypes and for the HER2 subtype., (© 2014 UICC.)

Background: Few previous studies of metabolic aberrations and prostate cancer risk have taken into account the fact that men with metabolic aberrations have an increased risk of death from causes other than prostate cancer. The aim of this study was to calculate, in a real-life scenario, the risk of prostate cancer diagnosis, prostate cancer death, and death from other causes., Methods: In the Metabolic Syndrome and Cancer Project, prospective data on body mass index, blood pressure, glucose, cholesterol, and triglycerides were collected from 285,040 men. Risks of prostate cancer diagnosis, prostate cancer death, and death from other causes were calculated by use of competing risk analysis for men with normal (bottom 84%) and high (top 16%) levels of each factor, and a composite score., Results: During a mean follow-up period of 12 years, 5,893 men were diagnosed with prostate cancer, 1,013 died of prostate cancer, and 26,328 died of other causes. After 1996, when prostate-specific antigen testing was introduced, men up to age 80 years with normal metabolic levels had 13% risk of prostate cancer, 2% risk of prostate cancer death, and 30% risk of death from other causes, whereas men with metabolic aberrations had corresponding risks of 11%, 2%, and 44%., Conclusions: In contrast to recent studies using conventional survival analysis, in a real-world scenario taking risk of competing events into account, men with metabolic aberrations had lower risk of prostate cancer diagnosis, similar risk of prostate cancer death, and substantially higher risk of death from other causes compared with men who had normal metabolic levels.

Purpose: Breast cancer can be classified into molecular subtypes that differ in clinical characteristics and prognosis. There is some but conflicting evidence that reproductive risk factors may differ between distinct breast cancer subtypes., Methods: We investigated associations of reproductive factors with the risk for six molecular breast cancer subtypes in a cohort of 21,532 Norwegian women who were born between 1886 and 1928 and followed up for breast cancer incidence between 1961 and 2008. We obtained stored tumor tissue from incident breast cancers and used immunohistochemistry and in situ hybridization to classify 825 invasive tumors into three luminal subtypes [Luminal A, Luminal B (HER2-) and Luminal B (HER2+)] and three non-luminal subtypes [human epidermal growth factor receptor 2 (HER2) subtype, basal-like phenotype (BP) and five negative phenotype (5NP)]. We used Cox regression to assess reproductive factors and risk for each subtype., Results: We found that young age at menarche, old age at first birth and low parity were associated with increased risk for luminal breast cancer subtypes. For the HER2 subtype, we either found no association or associations in the opposite direction compared to the luminal subtypes. The BP subtype appeared to have a similar reproductive risk profile as the luminal subtypes. Breastfeeding was associated with a reduced risk for HER2 and 5NP subtypes, but was not associated with any other subtype., Conclusions: The results suggest that molecular breast cancer subtypes differ in their reproductive risk factors, but associations with non-luminal subtypes are still poorly understood and warrant further study.

Background: We investigated perinatal factors in relation to bone cancer subtypes, osteosarcoma (OS), Ewing Sarcoma (ES) and chondrosarcoma (CS)., Materials and Methods: All cases in Norway (1970-2009), Sweden (1974-2009) and Denmark (1980-2010)<43 years were included (n=914); 10 controls per case were selected from birth registries (which provided information on pregnancies) matched on birth country, sex and birth year (n=9140). Unconditional logistic regression models including sex and birth year were used to compute relative risk (RR) and 95% confidence intervals (CI)., Results: Higher maternal education was associated with a 40% increase in OS risk (95% CI 1-93%). The RR for OS was 3.22 (95% CI 1.37-7.59) comparing offspring of hypertensive mothers with those of mothers with a normotensive pregnancy, and Cesarean section was associated with a 29% risk reduction (95% CI 0-50%). When gestational age, birth weight and birth length were assessed simultaneously, there were no associations with any of the bone tumor subtypes., Conclusion: These results provided little evidence of an important role of pregnancy factors in the etiology of bone cancers. Higher maternal education may be associated with factors, possibly early nutrition or other correlates of socioeconomic status, that increase OS risk in offspring. The elevated OS risk associated with gestational hypertension and reduced risk associated with Cesarean section warrant replication.

Background: We aimed to estimate lifetime cumulative risk of melanoma (CRM) in relatives of patients with melanoma by histology and age at diagnosis in patients and relatives., Methods: A population-based cohort of 238724 first-degree relatives of 46091 melanoma patients diagnosed in 1955-2010 in Nordic countries was followed for cancer incidence., Findings: The CRM (0-79 years) in first-degree relatives of a patient with superficial spreading (SSM), nodular (NM), or lentigo maligna melanoma was quite similar, ranging from 2.5% to about 3%, which represents about 2-fold increase over the general population risk. When one melanoma patient in the family was diagnosed before age 30, the CRM was about 3%. When there were > or =2 melanoma patients diagnosed before age 30 in a family, CRM for relatives was about 14%, 6% for diagnoses at age 30-59, and 5% for diagnoses at age 60 or older. Depending on age at diagnosis of same-sex twins (not known whether monozygotic/dizygotic), their CRM was about 7-21%. Although no familial case of concordant histological types of acral lentiginous/desmoplastic/compound nevus/spindle cell melanomas or malignant blue nevus was found, familial risks of discordant histological types of melanoma were interchangeably high for most of the types, e.g. higher risk of SSM when a first-degree relative had NM [standardized incidence ratios (SIR)=2.6, 95% confidence interval (CI)=2.1-3.3, n=72] or acral lentiginous (4.0, 95% CI=1.5-8.8, n=6) and vice versa. There was a tendency toward concordant age at diagnosis of melanoma among relatives of melanoma patients., Interpretation: Findings of this study may help clinicians to find subjects at high melanoma risk for the genetic counseling. The risk was highest when melanoma occurred in a same-sex twin, one first-degree relative diagnosed at young age (<30), or > or =2 first-degree relatives. Histological type of melanoma does not seem to play an important role in familial melanoma., Funding: This work was supported by the Nordic Cancer Union, Swedish Council for Working Life and Social Research, and German Cancer Aid., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: To assess the association between height and risk of cancer and cancer death., Methods: The metabolic syndrome and cancer project is a prospective pooled cohort study of 585,928 participants from seven cohorts in Austria, Norway, and Sweden. Hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer incidence and death were estimated in height categories and per 5-cm increment for each cancer site using Cox proportional hazards model., Results: During a mean follow-up of 12.7 years (SD = 7.2), 38,862 participants were diagnosed with cancer and 13,547 participants died of cancer. Increased height (per 5-cm increment) was associated with an increased overall cancer risk in women, HR 1.07 (95 % CI 1.06-1.09), and in men, HR 1.04 (95 % CI 1.03-1.06). The highest HR was seen for malignant melanoma in women, HR 1.17 (95 % CI 1.11-1.24), and in men HR 1.12 (95 % CI 1.08-1.19). Height was also associated with increased risk of cancer death in women, HR 1.03 (95 % CI 1.01-1.16), and in men, HR 1.03 (95 % CI 1.01-1.05). The highest HR was observed for breast cancer death in postmenopausal women (>60 years), HR 1.10 (95 % CI 1.00-1.21), and death from renal cell carcinoma in men, HR 1.18 (95 % CI 1.07-1.30). All these associations were independent of body mass index., Conclusion: Height was associated with risk of cancer and cancer death indicating that factors related to height such as hormonal and genetic factors stimulate both cancer development and progression.

Methyl group donors and intermediates of one-carbon metabolism affect DNA synthesis and DNA methylation, and may thereby affect prostate carcinogenesis. Choline, the precursor of betaine, and the one-carbon metabolite sarcosine have been associated with increased prostate cancer risk. Within JANUS, a prospective cohort in Norway (n = 317,000) with baseline serum samples, we conducted a nested case-control study among 3,000 prostate cancer cases and 3,000 controls. Using conditional logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) for prostate cancer risk were estimated according to quintiles of circulating betaine, dimethylglycine (DMG), sarcosine, glycine and serine. High sarcosine and glycine concentrations were associated with reduced prostate cancer risk of borderline significance (sarcosine: highest vs. lowest quintile OR = 0.86, CI = 0.72-1.01, p(trend) = 0.03; glycine: OR = 0.83, CI = 0.70-1.00, p(trend) = 0.07). Serum betaine, DMG and serine were not associated with prostate cancer risk. However, individuals with a high glycine/serine ratio were at decreased prostate cancer risk (OR = 0.74, CI = 0.69-0.85, p(trend) < 0.001). This population-based study suggested that men with high serum sarcosine or glycine concentrations have modestly reduced prostate cancer risk. Ratios of metabolites reflecting one-carbon balance may be associated with prostate cancer risk, as demonstrated for the glycine/serine ratio, and should be explored in future studies., (© 2013 UICC.)

Objective: The etiology of childhood cancers is largely unknown. Studies have suggested that birth characteristics may be associated with risk. Our goal was to evaluate the risk of childhood cancers in relation to fetal growth., Methods: We conducted a case-control study nested within Nordic birth registries. The study included cancer cases diagnosed in Denmark, Finland, Norway, and Sweden among children born from 1967 to 2010 and up to 10 matched controls per case, totaling 17,698 cases and 172,422 controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were derived from conditional logistic regression., Results: Risks of all childhood cancers increased with increasing birth weight (P trend ≤ .001). Risks of acute lymphoid leukemia and Wilms tumor were elevated when birth weight was >4000 g and of central nervous system tumors when birth weight was >4500 g. Newborns large for gestational age were at increased risk of Wilms tumor (OR: 2.1 [95% CI: 1.2-3.6]) and connective/soft tissue tumors (OR: 2.1 [95% CI: 1.1-4.4]). In contrast, the risk of acute myeloid leukemia was increased among children born small for gestational age (OR: 1.8 [95% CI: 1.1-3.1]). Children diagnosed with central nervous system tumors at <1 year of age had elevated risk with increasing head circumference (P trend < .001). Those with head circumference >39 cm had the highest risk (OR: 4.7 [95% CI: 2.5-8.7])., Conclusions: In this large, Nordic population-based study, increased risks for several childhood tumors were associated with measures of fetal growth, supporting the hypothesis that tumorigenesis manifesting in childhood is initiated in utero.

Reproductive factors, including early age at menarche, late age at first birth, low parity, and late age at menopause, are associated with increased risk of breast cancer, but it is not clear to which degree the associations persist into old age. Altogether 58,426 Norwegian women born between 1886 and 1928 were followed up for breast cancer incidence from 1961 to 2008. Associations of reproductive factors with breast cancer risk were analyzed separately for the age intervals 55-69 and 70 years and older, using Cox regression. The associations were of similar strength in the two age strata. At 70 years and later, hazard ratios (HR) for the following comparisons were found: late (≥17 years) versus early (<13 years) age at menarche [HR 0.79, 95 % confidence interval (CI): 0.62, 1.01, P for trend <0.001]; late (≥35 years) versus early (<20 years) age at first birth (HR 1.54, 95 % CI: 1.13, 2.11, P for trend <0.001); high (≥5) versus low (1) parity (HR 0.68, 95 % CI: 0.54, 0.86, P for trend = 0.001) and late (50-54 years) versus early (<45 years) age at menopause (HR 1.44, 95 % CI: 1.10, 1.90, P for trend = 0.002). These findings suggest that reproductive events may have life-long effects on breast cancer risk.

Background: Although individual studies have been inconsistent, meta-analyses of epidemiological data suggest that high folate and vitamin B12 levels may be associated with increased prostate cancer risk., Methods: Within JANUS, a prospective cohort in Norway (n = 317 000) with baseline serum samples, we conducted a nested case-control study among 3000 prostate cancer cases and 3000 controls, matched on age and time at serum sampling, and county of residence. Using conditional logistic regression, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer risk were estimated according to quintiles of serum folate, vitamin B12, methylmalonic acid (MMA), total homocysteine (tHcy) and methionine, and according to MTHFR 677C→T genotypes. To correct for degradation during sample storage, folate concentration was measured as p-aminobenzoylglutamate (pABG) equivalents following oxidation and acid hydrolysis., Results: We observed a weak positive association between folate concentration and prostate cancer risk [OR highest vs lowest quintile = 1.15 (0.97-1.37), P-trend = 0.04], which was more pronounced among individuals ≥ 50 years at inclusion [OR 1.40 (1.07-1.84), P-trend = 0.02]. tHcy showed an inverse trend with risk [OR 0.92 (0.77-1.10), P-trend = 0.03]. Vitamin B12, MMA and methionine concentrations were not associated with prostate cancer risk. Compared with the MTHFR 677CC genotype, the CT and TT variants, both of which were related to lower folate concentrations, were associated with reduced prostate cancer risk [OR 0.82 (0.72-0.94) and OR 0.78 (0.64-0.94), respectively]., Conclusion: This large-scale population-based study suggests that high serum folate concentration may be associated with modestly increased prostate cancer risk. We did not observe an association between vitamin B12 status and prostate cancer risk.

Background: Testicular germ cell tumour (TGCT) is the most common cancer in young men, and an imbalance between the estrogen and androgen levels in utero is hypothesized to influence TGCT risk. Thus, polymorphisms in genes involved in the action of sex hormones may contribute to variability in an individual's susceptibility to TGCT., Methods: We conducted a Norwegian-Swedish case-parent study. A total of 105 single-nucleotide polymorphisms (SNPs) in 20 sex hormone pathway genes were genotyped using Sequenom MassArray iPLEX Gold, in 831 complete triads and 474 dyads. To increase the statistical power, the analysis was expanded to include 712 case singletons and 3922 Swedish controls, thus including triads, dyads and the case-control samples in a single test for association. Analysis for allelic associations was performed with the UNPHASED program, using a likelihood-based association test for nuclear families with missing data, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. False discovery rate (FDR) was used to adjust for multiple testing., Results: Five genetic variants across the ESR2 gene [encoding estrogen receptor beta (ERβ)] were statistically significantly associated with the risk of TGCT. In the case-parent analysis, the markers rs12434245 and rs10137185 were associated with a reduced risk of TGCT (OR = 0.66 and 0.72, respectively; both FDRs <5%), whereas rs2978381 and rs12435857 were associated with an increased risk of TGCT (OR = 1.21 and 1.19, respectively; both FDRs <5%). In the combined case-parent/case-control analysis, rs12435857 and rs10146204 were associated with an increased risk of TGCT (OR = 1.15 and 1.13, respectively; both FDRs <5%), whereas rs10137185 was associated with a reduced risk of TGCT (OR = 0.79, FDR <5%). In addition, we found that three genetic variants in CYP19A1 (encoding aromatase) were statistically significantly associated with the risk of TGCT in the case-parent analysis. The T alleles of the rs2414099, rs8025374 and rs3751592 SNPs were associated with an increased risk of TGCT (OR = 1.30, 1.30 and 1.21, respectively; all FDRs <5%). We found no statistically significant differences in allelic effect estimates between parental inherited genetic variation in the sex hormone pathways and TGCT risk in the offspring, and no evidence of heterogeneity between seminomas and non-seminomas, or between the Norwegian and the Swedish population, in any of the SNPs examined., Conclusions: Our findings provide support for ERβ and aromatase being implicated in the aetiology of TGCT. Exploring the functional role of the TGCT risk-associated SNPs will further elucidate the biological mechanisms involved.

Observational studies have shown inconsistent results for the association between blood pressure and cancer risk. We investigated the association in 7 cohorts from Norway, Austria, and Sweden. In total, 577799 adults with a mean age of 44 years were followed for, on average, 12 years. Incident cancers were 22184 in men and 14744 in women, and cancer deaths were 8724 and 4525, respectively. Cox regression was used to calculate hazard ratios of cancer per 10-mmHg increments of midblood pressure, which corresponded with 0.7 SDs and, for example, an increment of systolic/diastolic blood pressure of 130/80 to 142/88 mmHg. All of the models used age as the time scale and were adjusted for possible confounders, including body mass index and smoking status. In men, midblood pressure was positively related to total incident cancer (hazard ratio per 10 mmHg increment: 1.07 [95% CI: 1.04-1.09]) and to cancer of the oropharynx, colon, rectum, lung, bladder, kidney, malignant melanoma, and nonmelanoma skin cancer. In women, midblood pressure was not related to total incident cancer but was positively related to cancer of the liver, pancreas, cervix, uterine corpus, and malignant melanoma. A positive association was also found for cancer mortality, with HRs per 10-mmHg increment of 1.12 (95% CI: 1.08-1.15) for men and 1.06 (95% CI: 1.02-1.11) for women. These results suggest a small increased cancer risk overall in men with elevated blood pressure level and a higher risk for cancer death in men and women.

Background: The etiology of testicular germ cell cancer (TGCC) is still poorly understood, but biological and epidemiological evidence suggest that TGCC originates early in life. The aim of the present study was to analyze heterogeneity in TGCC risk within Norway, comparing county of birth to county of diagnosis, in order to assess the relative contribution of risk factors acting early and later in life. A further aim was to present the Norwegian TGCC incidence rates (1958-2007)., Material and Methods: All TGCC cases (n = 7130) reported to the Cancer Registry of Norway, 1958-2007, were analyzed by county of diagnosis in 10-year intervals. The relative risk of TGCC based on county of birth, was estimated by Poisson regression analysis of all new TGCC cases (n = 1943), based on the mother's county of residence at the time of the son's birth, 1967-2007, obtained by linkage between the Cancer Registry and the Medical Birth Registry of Norway., Results: Between the first (1958-67) and last (1998-2007) 10-year period, the average incidence rate more than tripled from 3.3 to 10.5 per 100 000 person-years (world adjusted), respectively. The average incidence rate during 1968-2007 was highest in the county of Rogaland (8.6) and lowest in Hedmark (5.3), the ratio between them being 1.6. The relative risk of TGCC based on county of birth (1967-2007) varied between 1.43 (Møre og Romsdal) and 0.95 (Buskerud), giving a ratio of 1.5., Conclusions: The ratio between the relative risk in the highest and lowest county was basically similar when comparing counties of birth with counties of diagnosis. Thus, our data do not shed light on the relative contribution of risk factors acting early versus later in life. The incidence rate of TGCC in Norway is among the highest in the world, and the increase in incidence rate does not seem to level off.

Objective: To quantify the separate contributions of menopausal hormone treatment and mammography screening activities on trends in incidence of invasive breast cancer between 1987 and 2008., Design: Population study using aggregated data analysed by an extended age-period-cohort model., Setting: Norway. Population Norwegian women aged 30-90 between 1987 and 2008, including 50,102 newly diagnosed cases of invasive breast cancer. Main outcomes measures Attributable proportions of mammography screening and hormone treatment to recent incidence of invasive breast cancer, and the remaining variation in incidence after adjustment for mammography screening and hormone treatment., Results: The incidence of invasive breast cancer in Norway increased steadily until 2002, levelled off, and then declined from 2006. All non-linear changes in incidence were explained by use of hormone treatment and mammography screening activities, with about similar contributions of each factor. In 2002, when the incidence among women aged 50-69 was highest, an estimated 23% of the cases in that age group could be attributed to mammography screening and 27% to use of hormone treatment., Conclusions: Changes in incidence trends of invasive breast cancer since the early 1990s may be fully attributed to mammography screening and hormone treatment, with about similar contributions of each factor.

Introduction: In contrast to research in adults, there have been limited studies on testicular germ-cell cancer among boys aged <15 years. The aim of the study was to investigate the association between perinatal characteristics and childhood testicular germ-cell cancer., Methods: We identified 152 patients with childhood germ-cell cancer among boys (<15 years) born in Norway, Sweden, Finland and Denmark between 1967 and 2006 using the cancer and medical birth registries. For each case we sampled 10 population controls matched on year and country of birth. We used conditional logistic regression analysis to estimate odds ratios for cancer risk., Results: There was a weak, positive association between high (≥4000 g) birth weight and childhood testicular germ-cell cancer (adjusted OR=1.25; 95% CI: 0.83-1.90) compared with normal birth weight, and a correspondingly elevated risk for low birth weight (adjusted OR=1.41; 95% CI: 0.43-4.56). For Ponderal Index (PI) there was an increased risk for low and high values compared to those in the middle category (adjusted OR=1.64; 95% CI: 1.03-2.62 and 1.67; 95% CI: 0.93-2.99), respectively. There was no association between birth length and childhood testicular germ-cell cancer. The adjusted OR for testicular cancer among first born was 1.40; 95% CI: 0.96-2.05. Greater maternal age and less maternal education appeared to increase the risk, but the estimates were not statistically significant., Conclusion: We found a U-shaped association between fetal growth, measured as the PI, and childhood testicular germ-cell cancer. Our findings support the notion that abnormal fetal growth rate confers a risk in pediatric testicular cancer [corrected]., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: The bimodality of the age-incidence curve of Hodgkin lymphoma (HL) has been ascribed to the existence of subgroups with distinct etiologies. Frailty models can be usefully applied to age-incidence curves of cancer to aid the understanding of biological phenomena in these instances. The models imply that for a given disease, a minority of individuals are at high risk, compared with the low-risk majority., Methods: Frailty modeling is applied to interpret HL incidence on the basis of population-based cancer registry data from the five Nordic countries for the period 1993 to 2007. There were a total of 8,045 incident cases and 362,843,875 person-years at risk in the study period., Results: A bimodal frailty analysis provides a reasonable fit to the age-incidence curves, employing 2 prototype models, which differ by having the sex covariate included in the frailty component (model 1) or in the baseline Weibull hazard (model 2). Model 2 seemed to fit better with our current understanding of HL than model 1 for the male-to-female ratio, number of rate-limiting steps in the carcinogenic process, and proportion of susceptibles; whereas model 1 performed better related to the heterogeneity in HL among elderly males., Conclusion: The present analysis shows that HL age-incidence data are consistent with a bimodal frailty model, indicating that heterogeneity in cancer susceptibility may give rise to bimodality at the population level, although the individual risk remains simple and monotonically increasing by age., Impact: Frailty modeling adds to the existing body of knowledge on the heterogeneity in risk of acquiring HL., (©2011 AACR)

Purpose: Cancer in a child may adversely affect parents' work opportunities due to enlarged care burdens and/or altered priorities. Few studies exist, and possible effects on parental employment and earnings were therefore explored., Materials and Methods: Data on the entire Norwegian population aged 27-65 with children under the age of 20 in 1990-2002 (N=1.2 million) was retrieved from national registries. Employment rates for parents of 3263 children with cancer were compared to those of parents with children without cancer by means of logistic regression models. Log-linear regression models were used to explore childhood cancer's effect on parental earnings for the large majority of parents who remained employed., Results: Cancer in a child was in general not associated with a reduced risk of employment, although some exceptions exist among both mothers and fathers. For employed mothers, CNS cancers, germinal cell cancers, and unspecified leukemia were associated with significant reductions in earnings (10%, 21%, and 60%, respectively). Reductions were particularly pronounced for mothers with a young and alive child, and became more pronounced with time elapsed from diagnosis. Fathers' earnings were not affected significantly., Discussion and Conclusion: Parents' employment is not adversely affected by a child's cancer in Norway. Earnings are reduced in certain instances, but the overall effects are minor. Generous welfare options and flexible labor markets typical for Nordic welfare states may account for this. In line with traditional caregiving responsibilities, reductions in earnings were most pronounced for mothers., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

As mammography screening aims to improve the prognosis through earlier detection/treatment, tumour progression and screening test sensitivity (STS) represent key parameters in the evaluation of screening programs. We will here study some methods for estimation of tumour progression and STS, and show how previously used methods can be combined and developed to utilise more of the data available in modern screening programs. Weedon-Fekjaer et al. recently suggested a study design using interview data about time since previous screening to estimate tumour progression and STS in a stepwise Markov model. While useful, the approach does not utilise tumour size measurements, nor link tumour progression to tumour size. Hence, we will here propose formulas for estimating tumour progression and STS using a continuous tumour growth model. To estimate tumour progression and STS, tumour growth curves are followed from one screening to the next, and probabilities for all combinations of tumour sizes at repeated screening examinations calculated. Based on the probabilities for screening detection on subsequent screening examinations, maximum likelihood estimates are calculated. Applied to Norwegian data, the new approach gives similar results to previously published results based on interval data, confirming the earlier estimated large variation in tumour growth rates.

Background: Physical activity appears to be inversely related to cancer risk, although the evidence is convincing for colon cancer only. As physical activity levels are difficult to measure in the general population, we aimed to investigate how physical activity influences cancer risk using a cohort of Norwegian world class athletes., Methods: The cohort includes 3,428 athletes. Individual questionnaires gave information about physical activity and lifestyle variables until attained age. To elucidate the level of cancer risk, groups of athletes were compared to the general population (external comparisons) and to each other (internal comparisons)., Results: A slightly reduced risk of total cancer was observed in the cohort of athletes, but stronger effects were observed for subgroups. The risk reduction was most pronounced for lung cancer and for leukemia/lymphoma. In women, a threefold increased risk of thyroid cancer was observed., Conclusion: This cohort of athletes seems to have a reduced risk of cancer. The beneficial association, however, is weak and may be attributed to healthy lifestyle as well as to physical activity. Prolonged strenuous exercise may also increase the risk of thyroid cancer in women.

Background: Body mass index (BMI) is an established risk factor for colon cancer, but risks may differ between genders and colon subsites. Moreover, whether weight change influences risk is not yet clarified. We investigated these issues in a large, Norwegian, population-based cohort study., Methods: Participants' weight was measured at examinations up to three times between 1974 and 1988. Hazard ratios (HR) and confidence intervals (CI) were estimated using Cox regression., Results: During follow-up of 38,822 men and 37,357 women, we identified 228 proximal and 174 distal colon cancer cases in men and 237 and 159 cases, respectively, in women. The association between BMI and colon cancer risk differed between subsites in men (P = 0.02) but not in women (P = 0.95). In men, HRs (95% CIs) per 5 kg/m(2) were 1.07 (0.86-1.33) and 1.49 (1.19-1.87) for proximal and distal colon, respectively. In women, corresponding HRs (95% CIs) were 1.15 (0.99-1.34) and 1.25 (1.05-1.49). Among overweight men (BMI > or = 25 kg/m(2)), weight gain > or = 10 kg gave higher colon cancer risk than weight maintenance (HR, 2.09; 95% CI, 1.21-3.63), whereas risks were similar among men with stable weight, weight loss, or gains <10 kg. Weight change was not associated with risk in women., Conclusions: The influence of BMI on colon cancer risk differed between subsites in men. Weight gains <10 kg did not influence risk., Impact: Our results support gender differences and the hypothesis of different etiologies for colon subsites. Whether weight loss in the overweight decreases risk of colon cancer warrants further study., (Copyright 2010 AACR.)

Metabolic components [body mass index (BMI), blood pressure, serum lipids] and physical activity may affect biological mechanisms of importance for breast cancer prognosis. A population-based survival study among 1,364 breast cancer cases within the Norwegian Counties Study during 1974-2005 was conducted. Pre-diagnostic measurements of BMI, blood pressure, serum lipids, and self-reported physical activity were assessed. Multivariable Cox proportional hazard models were used in analyses (SAS version 9.11). Among these breast cancer cases (age at diagnosis 27-79 years), 429 women died (8.2 mean follow-up years). Those with a BMI >or= 30 kg/m(2) had a 1.47 higher risk of dying during follow-up than women with a BMI of 18.5-25 kg/m(2) [hazard ratio (HR) = 1.47, 95% CI 1.08-1.99]. Women with BMI < 25 kg/m(2) and age of diagnosis >or=55 years had a 66% reduction in overall mortality if they regularly exercised before diagnosis compared with sedentary women (HR = 0.34, 95% CI 0.16-0.71). Women in the highest tertile of total cholesterol had a 29% increase in mortality compared to women in the lowest tertile (HR = 1.29, 95% CI 1.01-1.64). Additionally, women in the highest tertile of blood pressure had a 41% increase in mortality compared to women in the lowest tertile of blood pressure (HR = 1.41, 95% CI 1.09-1.83). Our study supports a relationship between mortality not only in relation to BMI, but also blood pressure, lipids, and physical activity among breast cancer patients. These factors may all be important targets for invention among breast cancer patients.

Purpose: The risk of developing bilateral kidney cancer has not been adequately defined in any large, population-based study with long-term follow-up to our knowledge., Patients and Methods: We estimated the risk of metachronous bilateral renal cell cancer in patients diagnosed with unilateral kidney cancer, as recorded in the nationwide cancer registries of Norway and Sweden. Altogether 28,642 patients were followed for an average of 4.4 years. The standardized incidence ratio--the ratio of the observed number of bilateral cancers to the number expected on the basis of the incidence in the Norwegian and Swedish population at large--was used as a measure of relative risk. We used multivariate Poisson regression to separate the effects of the explanatory variables., Results: A synchronous bilateral renal cell cancer was reported in 86 patients. A total of 112 metachronous bilateral cancers were recorded during 126,493 person-years of follow-up compared with 35.8 expected, yielding an overall relative risk (RR) of 3.1 (95% CI, 2.6 to 3.8) and a cumulative incidence of 0.8% after 20 or more years of follow-up. In the multivariate analyses, risk increased monotonically with younger age at first diagnosis (P for trend < .001); compared with patients who were 60 years or older, those younger than 40 years were at a 17-fold higher risk (RR = 17.4; 95% CI, 10.1 to 29.8). We also found a modest but statistically significant decreasing trend with increasing duration of follow-up., Conclusion: The risk of metachronous bilateral renal cell cancer is drastically higher among patients first affected at a young age, suggesting a subset of early onset renal cell cancer with a strong genetic component.

Background: Leukemia incidence in childhood has been shown to increase with birth weight. The purpose of this paper is to study whether the incidence of other childhood cancers also increases with birth weight., Methods: The Norwegian Medical Birth Registry was linked to the Norwegian Cancer Registry. The data consisted of 1.65 million children, of whom 3252 had a cancer diagnosis before age 16 years. The diagnoses were divided into 1010 leukemia cases, 870 cancer cases of the central nervous system (CNS), and 1370 remaining cancers., Results: The increase in hazard rate for all cancers with a 1 kg increase in birth weight was 1.23 (95% confidence interval = 1.14-1.32) after adjustment. For leukemia the increase was 1.29 (1.14-1.47), for CNS cancers 1.07 (0.93-1.23), and for the remaining cancer diagnoses 1.29 (1.16-1.40)., Conclusions: There seems to be a general relationship between heavier birth weight and cancer incidence in childhood.

Background: Human chorionic gonadotropin (hCG) is a pregnancy-specific hormone, proposed to be involved in the protective effect against breast cancer afforded to mothers who bear children. In comparison with normal pregnancies, Down syndrome pregnancies are characterized by further elevated hCG concentrations from late first trimester to the middle of the second trimester. This study aimed to compare the risk of breast cancer in women who gave birth to a child with Down syndrome (as a marker of elevated hCG exposure) with that of women who had only unaffected children., Methods: The study cohort included all mothers of live-born children in Norway and Sweden from 1967-1973 through 2004. During the study period, 54,063 women developed breast cancer; 5330 children with Down syndrome were born and 139 breast cancer cases were diagnosed in their mothers. We fitted Cox proportional hazards regression models to obtain relative risks of breast cancer, adjusted for risk factors for breast cancer, such as overall parity and age at births., Results: Mothers of Down syndrome children were at 23% increased risk to develop breast cancer (95% confidence interval = 4%-46%). The risk increase was limited to women who had a Down syndrome child after age 30, and seemed to be confined to women whose cancer was diagnosed before age 50., Conclusions: Study results do not support the hypothesis of a protective effect of elevated pregnancy hCG on maternal breast cancer.

Background: There are limited data available on tumour subtype-specific familial risks for nervous-system tumours. We aimed to provide such data at the population level., Methods: We used data from the nationwide Swedish and Norwegian databases on familial cancer to calculate standardised incidence ratios (SIRs) for the familial risk of developing a nervous-system tumour in offspring born after 1931 (Sweden) or 1900 (Norway) whose parents or siblings were probands., Findings: 54 195 patients had nervous-system tumours, 22 331 of whom belonged to the offspring generation aged 0-72 years in Sweden and 0-51 years in Norway. Of 709 familial patients in the offspring generation, 438 (61.8%) had a parent affected by a nervous-system tumour (SIR 1.66; 95% CI 1.51-1.82), 236 (33.3%) had a sibling affected by a nervous-system tumour (SIR 2.01; 95% CI 1.76-2.28), and 35 (4.9%) belonged to families with a parent and at least two siblings affected by a nervous-system tumour (multiplex families; SIR 13.40; 95% CI 9.33-18.66). The SIR for glioma was 1.8 (1.5-2.0) when a parent was a proband, but increased to 11.2 (5.7-19.5) in multiplex families. Early-onset neurinoma and haemangioma showed high familial risks; with an SIR for neurinoma of 1.7 (1.4-2.2) for offspring of affected parents, 2.7 (2.0-3.5) for siblings, and 27.2 (13.5-48.8) for multiplex families, and an SIR for haemangioma of 2.4 (1.4-3.8) for offspring of affected parents. Histology-specific population-based familial risks were shown for meningioma (1.6 for offspring of affected parents; 95% CI 1.3-2.0), ependymoma (2.7 for young offspring <20 years; 1.1-5.5), medulloblastoma (4.1 for siblings; 1.7-8.1), and neuroblastoma (3.2 for siblings; 1.1-6.9)., Interpretation: Our results suggest a complex genetic background for nervous-system tumours, which differs depending on the age of onset and histological subtype of the tumour. High sibling risks might suggest recessive inheritance. As the high-penetrant multiplex families only accounted for about 5% of familial nervous-system tumours, most familial cases are probably caused by low-penetrance genes., Funding: The Nordic Cancer Union, Deutsche Krebshilfe, the Swedish Cancer Society, and the Swedish Council for Working Life and Social Research.

Background: Adult height and insulin are thought to modify the development of breast cancer. However, little is known about the association between height and 17beta-estradiol, a key factor in breast carcinogenesis, and whether insulin modifies such an association., Methods: Among 204 healthy women, ages 25 to 35 years, who participated in the Energy Balance and Breast Cancer Aspect I study, adult height (in centimeters) and fasting serum concentrations of insulin (pmol/L) were measured. 17beta-Estradiol concentrations were measured in daily saliva samples throughout an entire menstrual cycle through RIA. Age and multivariate linear regression models were used to study the association between adult height and 17beta-estradiol levels throughout an entire menstrual cycle and whether serum levels of fasting insulin may modify such an association., Results: The women had a mean age of 30.7 years, adult height of 166.9 cm, and serum insulin of 85.7 pmol/L. For each increase of one SD in insulin levels in the upper tertile of adult height, the adjusted level of 17beta-estradiol increased by 3.1 pmol/L (95% confidence interval, 1.1-5.2), equivalent to a 17.3% higher mean average concentration of 17beta-estradiol. Women with an adult height > or =170 cm (upper tertile) and insulin levels >101 pmol/L (upper quartile) experienced, on average, 41% higher 17beta-estradiol levels throughout the entire menstrual cycle compared with women with the same adult height and insulin levels <101 pmol/L., Conclusion: Our findings support that premenopausal levels of 17beta-estradiol vary in response to adult height and insulin levels, of possible importance for breast cancer risk.

It is well known that men with testicular cancer also have reduced fertility before diagnosis. It is unclear, however, whether their parents also have reduced fertility. We performed a population-based record linkage study comparing parental fertility among 3711 testicular cancer cases and 371 100 control males. The cases were diagnosed from 1961 to 2001, and the data were analysed by logistic regression. Included indicators of parental fertility were number of children, rate of unlike-sex twins as a proxy for dizygotic twinning rate, and proportion of boys. The number of children was reduced across increasing sibship size among both mothers [odds ratio (OR) = 0.95, p(trend) = 0.003] and fathers [OR = 0.97, p(trend) = 0.057] of subjects with testicular cancer. The proportion of unlike-sex twins was also reduced among their mothers [(OR = 0.56, p = 0.049 (adjusted for year of birth)] and fathers [(OR = 0.56, p = 0.049 (adjusted for year of birth)]. The results were only marginally changed when also adjusting for respective parental age. Our study indicates that parents of testicular cancer cases have reduced fertility. This suggests that genetic factors are important in the association between testicular cancer and reduced fertility.

In this population-based Norwegian cohort study (2.1 million children), the impact of birth and parental characteristics on the risk of neuroblastoma (178 cases) was evaluated. In children below the age of 18 months, there was an increased neuroblastoma risk among those with congenital malformations and suggestion of increased risk when the mother had pre-eclampsia.

Introduction: Increased attention is being paid to the long-term health and well-being of people living with a history of cancer. Of particular concern is cancer's effect on productivity and work ability, which in turn is important for persons' financial situation, life satisfaction, and social relationships. We explored the extent to which Norwegian cancer survivors stay affiliated to working life compared to the cancer-free population, and quantified cancer-associated earning declines., Methods and Results: Logistic regression models were estimated to explore the impact of cancer on employment using register data covering the entire Norwegian population in 2001, 567,000 men and 549,300 women 40-59 years old, of whom 34,000 were diagnosed with cancer. These analyses revealed that a cancer diagnosis was strongly associated with not being employed. Log-linear regression models were used to estimate the effect of cancer on labor earnings in 2001 for those employed. Cancer was associated with a 12% decline in earnings overall. Leukemia, lymphomas, lung, brain, bone, colorectal, and head-and-neck cancer resulted in the largest reductions in employment and earnings. Earning declines were strongly associated with educational level. In addition, linear regression models were used to estimate differentials in earnings before and after cancer. These results accorded well with those from cross-sectional models., Conclusion and Implications for Cancer Survivors: Cancer survivors are less likely to be employed than the cancer-free population, and undertake modifications in their employment, e.g. reduce work-hours or hold lower-wage jobs, which result in reduced earnings. A social class gradient is present and must be addressed to accommodate appropriate intervention from welfare societies.

Background: High circulating levels of insulin-like growth factor (IGF-I) may elevate the risk of breast cancer in premenopausal women, possibly by increasing cell proliferation and reducing apoptosis., Methods: We conducted a nested case-control study among 35,105 Norwegian women who participated in a health screening survey, ages 40 to 42 years, and who were subsequently followed for a mean period of 4.3 years. During this period, 325 women were diagnosed with breast cancer; 647 women without breast cancer, matched on age and time of blood sampling, were selected as controls. Serum concentrations of IGF-I and its main binding protein (IGFBP-3) were measured with radioimmunoassay, and logistic regression analysis was used to adjust for relevant covariates., Results: The mean age at blood collection was 41.1 years in both groups, and the mean age at diagnosis for the cases was 45.4 years (range, 40-51 years). The median IGF-I level did not differ between cases (205 ng/mL) and controls (202 ng/mL). When analyzed by categories of serum IGF-I, the relative risk for women in the highest versus the lowest quintile was 1.46 (95% confidence interval, 0.93-2.32; P(trend) = 0.15) after adjusting for serum IGFBP-3, age, and year of blood collection. The exclusion of cases that were diagnosed within 2 years after blood collection did not materially affect the results., Conclusion: We found only a modest positive association between serum IGF-I levels and risk of breast cancer in women younger than 50 years of age.

Background: Cancer and birth defects may share factors that influence risk. A malformation may involve physiologic changes or changes in lifestyle that might affect cancer risks., Methods: In Norway and Sweden, the population-based medical birth and cancer registries were linked to identify subsequent cancer occurrence in children with birth defects and among their parents and siblings. Altogether, 5.2 million children and their families were included. The standardized incidence ratio (SIR) served as a measure of relative risk., Results: There was an increased overall cancer risk in individuals with birth defects in the two countries [SIR, 1.7; 95% confidence interval (95% CI), 1.6-1.9], and the increased risk remained into early adulthood. Individuals with malformations in the nervous system were at increased risk of developing cancer in the brain/nervous system (Norway: SIR, 58; 95% CI, 41-80; Sweden: SIR, 8.3; 95% CI, 4.0-15), individuals with Down syndrome were at an increased risk of leukemia (Norway: SIR, 36; 95% CI, 26-48; Sweden: SIR, 36; 95% CI, 28-46), and there was an increased overall cancer risk for individuals with multiple birth defects (Norway: SIR, 5.5; 95% CI, 3.3-8.7; Sweden: SIR, 3.6; 95% CI, 2.2-5.4). There was no increased overall cancer risk among mothers (SIR, 1.0; 95% CI, 1.0-1.0), fathers (SIR, 1.0; 95% CI, 0.9-1.0), and siblings (SIR, 1.0; 95% CI, 0.9-1.1) of children with birth defects., Conclusions: We observed an increased overall cancer risk in individuals with birth defects. The highest risks were seen for individuals with malformations in the nervous system, Down syndrome, and multiple defects. No increased overall cancer risk was seen among their parents or siblings.

Objectives: Mean sojourn time (MST) and screening test sensitivity (STS), is usually estimated by Markov models using incidence data from the first screening round and the interval between screening examinations. However, several screening programmes do not have full registration of cancers submerging after screening, and increased use of opportunistic screening over time can raise questions regarding the quality of interval cancer registration. Methods/settings Based on the earlier used Markov model, formulas for expected number of cases given time since former screening activity was developed. Using questionnaire data for 336,533 women in the Norwegian Breast Cancer Screening Programme (NBCSP), mean square regression estimates of MST and STS were calculated., Results: In contrast to the previously used method, the new approach gave satisfactory model fit. MST was estimated to 5.6 years for women aged 50-59 years, and 6.9 years for women aged 60-69 years, and STS was estimated to 55% and 60%, respectively. Attempts to add separate parameters for breast cancer incidence without screening, or previous STS, resulted in wide confidence intervals if estimated separately, and non-identifiably if combined., Conclusion: Previously published results of long MST and low screen test sensitivity were confirmed with the new approach. Questionnaire data on time since previous screening can be used to estimate MST and STS, but the approach is sensitive to relaxing the assumptions regarding the expected breast cancer incidence without screening and constant STS over time.

Trends in incidence and mortality rates of prostate cancer were analyzed using data from the national cancer registries of Denmark, Finland, Iceland, Norway, and Sweden. Joinpoint regression models were used to quantify temporal trends for the period from 1980 to 2004. Incidence rates were increasing and similar in the Nordic countries during the 1980s. Around 1990, a more rapid incidence increase began in all Nordic countries except Denmark, where an increase was seen 5 years later. In 2001, incidence rates in Denmark were half of those seen in the other Nordic countries, but mortality rates varied only marginally among countries. Mean annual declines in prostate cancer mortality of 1.9% (95% CI = 0.4% to 3.3%) and 1.8% (95% CI = 0.5% to 3.0%) were observed from 1996 to 2004 in Finland and Norway, respectively. During the same period, mortality rates leveled off in Iceland and Sweden but continued to increase in Denmark. The rapid increase in incidence during the early 1990s coincided with the introduction of the prostate-specific antigen (PSA) test and conveys little information about the occurrence of potentially lethal disease. Mortality rates, however, have recently stabilized or declined in countries where PSA testing and curative treatment have been commonly practiced since the late 1980s. Although other explanatory factors may be in operation, these trends are consistent with a moderate effect of increased curative treatment of early diagnosed prostate cancer and improved treatment of more advanced disease.

Many cancer forms today have good prognosis, and parenthood after cancer diagnosis and treatment has become a central research topic. Previous research has mainly focused on reproductive cancers, and few population-based studies exist. The effect of several cancer forms on fertility at a population level was explored. Discrete-time hazard regression models were used to analyse register and census data for complete Norwegian birth cohorts. Men and women 17-44 years in the period 1965-2001 were included. Models for first- and higher-order birth rates, for men and women, were estimated.Overall, first-birth rates among persons with cancer were reduced by only about 25% when compared with the general population. Male cancer survivors' second- and third-birth rates were similarly reduced, whereas higher-order birth rates for females were 36% below those of the general population. Significant decreases in cancer survivors' fertility disadvantage relative to the general population were seen from 1965 to 2001. Reductions in fertility were most pronounced for reproductive cancer forms, presumably related to subfecundity. However, also cancer forms unrelated to reproductive function led to reduced fertility, perhaps suggesting underlying social mechanisms. This is further supported by the difference in probability between first and subsequent births observed for women., ((c) 2007 John Wiley & Sons, Ltd.)

A positive association between overweight/obesity and endometrial cancer has been observed. It has been hypothesized that obesity is mostly associated with a subtype described as estrogen-dependent (Type I tumors), constituting about 80% of the endometrial tumors. Few epidemiologic studies have, however, analyzed different histological subtypes separately. The present study aimed at exploring the relations between body size and histological subtypes of cancer of the uterine corpus. Height and weight were measured in over 1 million Norwegian women aged 20-74 during 1963-2001. During follow-up, 9,227 cancers of the uterine corpus were diagnosed. The tumors were classified as Type I tumors (mostly endometrial adenocarcinomas with subgroups), Type II tumors (papillary, serous, and clear cell adenocarcinomas and some poorly differentiated carcinomas), sarcomas, and mixed tumors. Relative risks (RRs) of cancer of the uterine corpus were estimated using Cox proportional hazards regression. Compared with women with normal BMI, overweight and obese women had an overall RR of cancer of the uterine corpus of 1.36 (95% CI: 1.29-1.42) and 2.51 (95% CI: 2.83-2.66). The increase in risk was most pronounced for Type I tumors, but was also seen for Type II tumors, sarcomas and mixed tumors. The overall RR of corpus uteri cancer associated with a 10-cm increase in height was 1.09 (95% CI: 1.05-1.13), and was mostly observed for Type I tumors., ((c) 2006 Wiley-Liss, Inc.)

Reports on the association between obesity and lymphohematopoietic malignancies (LHMs) have been inconsistent. The present study aimed at exploring this association for specific disease lymphohematopoietic entities in a large Norwegian cohort. Height and weight were measured in two million Norwegian men and women aged 20-74 years during 1963-2001. During follow-up, 24,500 cases of LHMs were observed. Relative risks of disease were estimated by Cox proportional hazards regression. The risk of LHMs overall increased moderately by increasing body mass index and height in both sexes. The relative risk of LHMs per five-unit increase in body mass index was 1.11 (95% confidence interval (CI): 1.08, 1.14) in men and 1.08 (95% CI: 1.05, 1.11) in women. For each 10-cm increase in height, the relative risk was 1.19 (95% CI: 1.16, 1.22) in men and 1.16 (95% CI: 1.12, 1.20) in women. Separate analyses for different lymphohematopoietic malignancies did not reveal any group's being particularly strongly associated with body mass index. A modest increase in the risk of LHMs combined was observed with increasing height. The moderate associations between height and body mass index and LHMs found in the present study indicate that the observed increase in overweight/obesity plays only a minor role in explaining the increase in the incidence of LHMs.

The present study aimed at exploring the relations between body mass index (BMI) and stature and testicular cancer in a huge Norwegian cohort with measured height and weight. Height and weight were measured in 600,000 Norwegian men aged 14-44 years during 1963-2001. Results from parts of the study cohort have been reported previously. During follow-up, 1,357 testicular cancers were registered. Relative risks (RRs) of testicular cancer were estimated using Cox proportional hazards regression. The risk of testicular cancer decreased with adult BMI. Compared with men with normal BMI, overweight and obese men had a relative risk of cancer of 0.89 (95% CI: 0.77-1.03) and 0.83 (95% CI: 0.58-1.17). The relative risk of testicular cancer per unit increase in BMI was 0.97 (95% CI: 0.95-1.00). The risk of testicular cancer was not associated with adolescent BMI. A moderate increase in risk of seminomas was seen with increasing adult height. Compared with men with height 170-79 cm, men with height 180 cm and above had a relative risk of 1.17 (95% CI: 1.00-1.37).

We investigated relations between measured body mass index (BMI) and stature and thyroid cancer (3046 cases) in a large Norwegian cohort of more than two million individuals. The risk of thyroid cancer, especially of the papillary and follicular types, increased moderately with increasing BMI and height in both sexes.